MEDI 309 |
| Various approaches for Computer-Aided Drug Design are followed depending on the amount of computer time required, and the number of compounds examined. Our fastest approach is based on initial designs created with the ligand-growing program BOMB, which rapidly constructs combinatorial libraries given the structure of the target protein, a selected molecular scaffold and a set of substituents. The program performs a thorough conformational search in the binding site, and the binding affinity is estimated using scoring functions. The QikProp program is applied to filter all produced molecules to insure that they have drug-like properties. Additionally, BOMB allows for the use of custom scoring functions based on SAR data. Alternative starting motifs are pursued through multiple-copy simulations with small molecular probes to seek consensus binding sites. The lead refinement phase is usually performed using more precise, albeit slower MC/FEP simulations with MCPRO, including explicit solvation and extensive sampling to hone the predictions for the best scoring leads. This approach is also utilized extensively to address the activity loss due to mutations in the protein target. In our laboratories, the drug development program is being fully pursued through these multiple computational routes, followed by synthesis and biological assays. Recent methodological advances and general issues based on our experiences with molecule docking, growing, fragment simulations, ADME-properties evaluation, similarity searching, and free-energy perturbation calculations, and some representative applications will be presented with emphasis on inhibitor development for HIV reverse transcriptase. References: "The Many Roles of Computation in Drug Discovery." Jorgensen, W. L., Science 303, 1813-1818 (2004). "Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase." Jorgensen W. L.; Ruiz-Caro J.; Tirado-Rives J.; Basavapathruni A.; Anderson K. S.; Hamilton A. D. Bioorg Med Chem Lett. 16, 663-667 (2006). |
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Parallel Medicinal Chemistry
9:00 AM-12:00 PM, Wednesday, 13 September 2006 Moscone Center -- Room 103, Oral
Division of Medicinal Chemistry |